Low density lipoprotein (LDL) lipid oxidation products promote atherogenesis by stimulating an inflammatory response in vascular tissue (refs. 1-3). A spectrum of oxidized LDL species contributes to the pathobiology of the atherogenic environment within the arterial wall. Products forming early in the process of LDL oxidation promote expression of inflammatory cytokines, cell adhesion molecules, and chemotactic and growth factors, leading to monocyte influx and macrophage foam cell formation in the arterial intima (refs. 2,3). Extensively oxidized LDL promotes expression of scavenger receptors on macrophages, accelerating foam cell formation, leading to entrapment of highly oxidized LDL within the artery wall, and resulting in cytotoxicity and endothelial dysfunction (ref. 4).
The presence of oxidized LDL within atherosclerotic lesions in a rabbit model and in humans has been demonstrated (refs. 4,5). At high doses the antioxidant probucol decreased arterial lesion size in animal models of atherosclerosis, and these effects were correlated with the ability of probucol to decrease oxidation of LDL in vivo (refs. 6,7). Lipophilic antioxidants such as butylated hydroxytoluene (BHT) and N,N'-diphenylphenylenediamine (DPPD) have been shown to decrease aortic lesions in rabbits and protect LDL from oxidation (refs. 8,9).